The lot-of-rods (lorp25bbtl) mutant was isolated in a genetic screen of mutagenized zebrafish for changes in rod patterning in the larval retina. lorp25bbtl mutants display an increase in the number of rods and a reduction in the number of UV cones, likely due to a cell fate change. This phenotype is the opposite of that exhibited by the Nri knockout mice, which demonstrate an increase in the number of short-wavelength- sensitive cones (S cones) and a reduced number of rods. Initial characterization of the mutant shows that lorp25bbtl is a hypomorphic allele of the transcription factor tbx2b, and acts cell-autonomously in photoreceptor fate determination. This application proposes molecular studies to uncover the specific functions of tbx2b in photoreceptor development. The following topics will be addressed: 1. Is tbx2b a direct transcriptional regulator of photoreceptor genes? To answer this question a reporter gene assay in cultured cells will be performed to evaluate transcriptional modulation by tbx2b in conjunction with other retinal transcription factors in various photoreceptor promoters. 2. Taking advantage of the UV-cone depleted phenotype in lorp25bbtl and to identify UV-cone specific genes, a microarray experiment comparing the gene expression profile of lorp25bbtl and WT adult retinas will be performed. Public Health Relevance: Heritable diseases are among the leading causes of blindness in developed countries. In the United States, an estimated 80 million people suffer potentially blinding eye disease and 1.3 million people are legally blind (National Center for Health Statistics, 1996). Given the importance of visual system diseases, the direct benefits of identifying genes in zebrafish that may be involved in human disease like photoreceptor development or retinal dystrophies are obvious. Previous characterization of the lorp25bbtl mutant suggested a genetic pathway that directly contrasts that affected in the human Enhanced-S-cone Syndrome. I believe that studying tbx2b, the gene affected in lorp25bbtl, and its role in retinal development will help to dissect the developmental pathway affected in this human syndrome and ultimately will increase our understanding of retinal development and physiology.